The invention herein is directed to a process for the preparation of a .gamma.-lactone of the formula ##STR2## wherein R.sup.5 is a protecting group selected from the group consisting of tosyl, pivaloyl or trityl. Such compounds are useful in the preparation of a single enantiomer of amino azanoradamantane.
The invention herein is further directed to a process for the preparation of compounds of the general formula ##STR3## wherein X represents halogen, R represents hydrogen or lower alkyl and D is an azanoradamantane moiety as discussed hereinafter. Such compounds are useful as 5-HT agonists and/or antagonists.
It is disclosed in U.S. Pat. No. 5,140,023 and U.S. Pat. No. 5,223,613 that such azanoradamantane compounds can be prepared by reacting a trans-1,2-dicarbomethoxy-4-methylenecyclopentane with sodium hydroxide, followed by reaction with an acid to produce trans-4-methylene-1,2-cyclopentane-dicarboxylic acid. The dicarboxylic acid is reacted with acetic anhydride to produce cis-tetrahydro-5-methylene-1H-cyclopenta[c]furan-1,3(3aH)-dione which is reacted with ammonia gas and methylene chloride to produce the ammonium salt. Reaction of the ammonium salt with acetyl chloride produces the amide which is reacted with lithium aluminum hydride and di-t-butyl dicarbonate to produce cis-1,1-dimethylethylhexahydro-5-methylene-cyclopenta[c]pyrrole-2(1H)-carb oxylate. The product is reacted with bis(p-toluenesulfonyl)-sulfodiimide to produce the p-toluenesulfonamide which is reacted with thexyl borane to produce an endo-alcohol. The endo-alcohol is reacted with p-toluenesulfonyl chloride to produce a tosylate which is reacted with trifluoroacetic acid and treated with Hunig's base to provide the p-toluenesulfonamide azacycle. The azacycle is reductively cleaved to produce the aminoazacycle which is coupled with a benzoic acid derivative under mixed anhydride conditions to give the protected benzamide azacycle. Deprotection by hydrolysis and treatment with hydrochloric acid produces the desired benzamide azacycles.
It would be desirable to provide a process for the production of such benzamide azacycles which process requires fewer steps and is thereby more efficient, is feasible for commercial scale-up and produces a single enantiomer (as opposed to a racemic mixture).